Metabolic syndrome and the urinary microbiome of patients undergoing percutaneous nephrolithotomy

Objective:To identify possible stone-promoting microbes,we compared the profiles of microbes grown from stones of patients with and without metabolic syndrome(MetS).The association between MetS and urinary stone disease is well established,but the exact pathophysiologic relationship remains unknown.Recent evidence suggests urinary tract dysbiosis may lead to increased nephrolithiasis risk.Methods:At the time of percutaneous nephrolithotomy,bladder urine and stone fragments were collected from patients with and without MetS.Both sample types were subjected to expanded quantitative urine culture(EQUC)and 16 S ribosomal RNA gene sequencing.Results:Fifty-seven patients included 12 controls(21.1%)and 45 MetS patients(78.9%).Both cohorts were similar with respect to demographics and non-MetS comorbidities.No controls had uric acid stone composition.By EQUC,bacteria were detected more frequently in MetS stones(42.2%)compared to controls(8.3%)(p=0.041).Bacteria also were more abundant in stones of MetS patients compared to controls.To validate our EQUC results,we performed 16 S ribosomal RNA gene sequencing.In 12/16(75.0%)sequence-positive stones,EQUC reliably isolated at least one species of the sequenced genera.Bacteria were detected in both“infectious”and“non-infectious”stone compositions.Conclusion:Bacteria are more common and more abundant in MetS stones than control stones.Our findings support a role for bacteria in urinary stone disease for patients with MetS regardless of stone composition.

Therapeutic Targeting of PKM2 Ameliorates NASH Fibrosis Progression in a Macrophage-Specific and Liver-Specific Manner

Nonalcoholic steatohepatitis(NASH)may soon become the leading cause of end-stage liver disease worldwide with limited treatment options.Liver fibrosis,which is driven by chronic inflammation and hepatic stellate cell(HSC)activation,critically determines morbidity and mortality in patients with NASH.Pyruvate kinase M2(PKM2)is involved in immune activation and inflammatory liver diseases;however,its role and therapeutic potential in NASH-related fibrosis remain largely unexplored.Bioinformatics screening and analysis of human and murine NASH livers indicated that PKM2 was upregulated in nonparenchymal cells(NPCs),especially macrophages,in the livers of patients with fibrotic NASH.Macrophage-specific PKM2 knockout(PKM2^(FL/FL)LysM-Cre)significantly ameliorated hepatic inflammation and fibrosis severity in three distinct NASH models induced by a methionine-and choline-deficient(MCD)diet,a high-fat high-cholesterol(HFHC)diet,and a western diet plus weekly carbon tetrachloride injection(WD/CCl_(4)).Single-cell transcriptomic analysis indicated that deletion of PKM2 in macrophages reduced profibrotic Ly6C^(high) macrophage infiltration.Mechanistically,PKM2-dependent glycolysis promoted NLR family pyrin domain containing 3(NLRP3)activation in proinflammatory macrophages,which induced HSC activation and fibrogenesis.A pharmacological PKM2 agonist efficiently attenuated the profibrotic crosstalk between macrophages and HSCs in vitro and in vivo.Translationally,ablation of PKM2 in NPCs by cholesterol-conjugated heteroduplex oligonucleotides,a novel oligonucleotide drug that preferentially accumulates in the liver,dose-dependently reversed NASH-related fibrosis without causing observable hepatotoxicity.The present study highlights the pivotal role of macrophage PKM2 in advancing NASH fibrogenesis.Thus,therapeutic modulation of PKM2 in a macrophage-specific or liver-specific manner may serve as a novel strategy to combat NASH-related fibrosis.

Classical bovine spongiform encephalopathy and chronic wasting disease:two sides of the prion coin

Transmissible spongiform encephalopathies(TSEs)are a group of progressive and ultimately fatal neurologic diseases of man and animals,all resulting from the propagated misfolding of the host's normal cellular prion protein.These diseases can be spontaneous,heritable,anthropogenic/iatrogenic,or in some cases horizontally transmissible,and include such notable TSEs as bovine spongiform encephalopathy(BSE)of cattle and chronic wasting disease(CWD)of cervids.Although they are both unequivocally protein misfolding disorders,they differ markedly in their pathogenesis,transmissibility,and zoonotic potential.While the BSE epidemic has largely abated over the past three decades following global feed bans on ruminant meat and bone meal,CWD,which is readily transmitted through various forms of excreta,has rapidly expanded from its original endemic zone to encompass much of North America,along with recently identified foci in Scandinavia.Most importantly,although the classical form of BSE has proven transmissible to humans consuming contaminated beef or beef products,so far there have been no conclusive reports on the zoonotic transmission of cWD to humans.The underlying basis for these differences-whether host or agent directed-are not well understood,though may be due to inherent differences in the three-dimensional structure of the misfolded BSE or CWD prion proteins or the expression levels and tissue distribution of respective cellular prion proteins.With the uncontrolled geographic spread of CWD,it is imperative that we improve our understanding of the factors governing prion disease pathogenesis,transmission,and zoonotic potential.

Geographical Distribution of Arboviruses, Aedes aegypti and Aedes albopictus Vectors and Their Resistance to Insecticides in Africa: A Systematic Review

Background & Objectives: Epidemics of arboviruses such as Dengue, Chikungunya and Zika have been recorded in recent years indicating that Aedes aegypti and Aedes albopictus are both important and very active vectors in Africa. For vector control, insecticides are on the front line, unfortunately, reported resistance jeopardizes the effectiveness of this strategy. The objective of this review was to determine the geographical distribution and insecticide resistance mechanisms of Ae. aegypti and Ae. Albopictus in Africa. Methods: A systematic review of the literature in scientific databases (PubMed, Google Scholar, ScienceDirect, Hinari) allowed us to identify relevant articles on the geographical distribution of Aedes aegypti, Aedes albopictus and arboviral diseases. On the other hand, studies related to insecticides used in vector control against Aedes, associated resistances and their molecular and metabolic mechanisms. Results: A total of 94 studies met the inclusion criteria for this search. Aedes aegypti is reported in most of Africa, and Aedes albopictus in part. There is a re-emergence and outbreak of Arbovirus epidemics in West and Central Africa. The insecticides used were organochlorines, carbamates, organophosphates and pyrethroids. In Aedes, target site insensitivity and metabolic resistance would be the 2 main mechanisms of resistance to these insecticides. Interpretation & Conclusion: Resistance has been recorded in all four major classes of insecticides recommended by WHO for vector control and eradication. New vector control methods such as the use of plant extracts with larvicidal and adulticidal activities, advanced modern biotechnology techniques, and nanobiotechnology need to be developed.

Clemastine in remyelination and protection of neurons and skeletal muscle after spinal cord injury

Spinal cord injuries affect nearly five to ten individuals per million every year. Spinal cord injury causes damage to the nerves, muscles, and the tissue surrounding the spinal cord. Depending on the severity, spinal injuries are linked to degeneration of axons and myelin, resulting in neuronal impairment and skeletal muscle weakness and atrophy. The protection of neurons and promotion of myelin regeneration during spinal cord injury is important for recovery of function following spinal cord injury. Current treatments have little to no effect on spinal cord injury and neurogenic muscle loss. Clemastine, an Food and Drug Administration-approved antihistamine drug, reduces inflammation, protects cells, promotes remyelination, and preserves myelin integrity. Recent clinical evidence suggests that clemastine can decrease the loss of axons after spinal cord injury, stimulating the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes that are capable of myelination. While clemastine can aid not only in the remyelination and preservation of myelin sheath integrity, it also protects neurons. However, its role in neurogenic muscle loss remains unclear. This review discusses the pathophysiology of spinal cord injury, and the role of clemastine in the protection of neurons, myelin, and axons as well as attenuation of skeletal muscle loss following spinal cord injury.

Regulation of enolase activation to promote neural protection and regeneration in spinal cord injury

Spinal cord injury(SCI)is a debilitating condition characterized by damage to the spinal cord resulting in loss of function,mobility,and sensation with no U.S.Food and Drug Administration-approved cure.Enolase,a multifunctional glycolytic enzyme upregulated after SCI,promotes pro-and anti-inflammatory events and regulates functional recovery in SCI.Enolase is normally expressed in the cytosol,but the expression is upregulated at the cell surface following cellular injury,promoting glial cell activation and signal transduction pathway activation.SCI-induced microglia activation triggers pro-inflammatory mediators at the injury site,activating other immune cells and metabolic events,i.e.,Rho-associated kinase,contributing to the neuroinflammation found in SCI.Enolase surface expression also activates cathepsin X,resulting in cleavage of the C-terminal end of neuron-specific enolase(NSE)and non-neuronal enolase(NNE).Fully functional enolase is necessary as NSE/NNE C-terminal proteins activate many neurotrophic processes,i.e.,the plasminogen activation system,phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B,and mitogen-activated protein kinase/extracellular signal-regulated kinase.Studies here suggest an enolase inhibitor,ENOblock,attenuates the activation of Rho-associated kinase,which may decrease glial cell activation and promote functional recovery following SCI.Also,ENOblock inhibits cathepsin X,which may help prevent the cleavage of the neurotrophic C-terminal protein allowing full plasminogen activation and phosphatidylinositol-4,5-bisphosphate 3-kinase/mitogen-activated protein kinase activity.The combined NSE/cathepsin X inhibition may serve as a potential therapeutic strategy for preventing neuroinflammation/degeneration and promoting neural cell regeneration and recovery following SCI.The role of cell membrane-expressed enolase and associated metabolic events should be investigated to determine if the same strategies can be applied to other neurodegenerative diseases.Hence,this review discusses the importance of enolase activation and inhibition as a potential therapeutic target following SCI to promote neuronal survival and regeneration.

Locked nucleic acid real-time polymerase chain reaction method identifying two polymorphisms of hepatitis B virus genotype C2 infections,rt269L and rt269I

BACKGROUND The presence of two distinct hepatitis B virus(HBV)Pol RT polymorphisms,rt269L and rt269I,could contribute to the unique clinical or virological phenotype of HBV genotype C2.Therefore,a simple and sensitive method capable of identifying both types in chronic hepatitis B(CHB)patients infected with genotype C2 should be developed.AIM To develop a novel simple and sensitive locked nucleic acid(LNA)-real timepolymerase chain reaction(RT-PCR)method capable of identifying two rt269 types in CHB genotype C2 patients.METHODS We designed proper primer and probe sets for LNA-RT-PCR for the separation of rt269 types.Using synthesized DNAs of the wild type and variant forms,melting temperature analysis,detection sensitivity,and endpoint genotyping for LNA-RT-PCR were performed.The developed LNA-RT-PCR method was applied to a total of 94 CHB patients of genotype C2 for the identification of two rt269 polymorphisms,and these results were compared with those obtained by a direct sequencing protocol.RESULTS The LNA-RT-PCR method could identify two rt269L and rt269I polymorphisms of three genotypes,two rt269L types[‘L1’(WT)and‘L2’]and one rt269I type(‘I’)in single(63 samples,72.4%)or mixed forms(24 samples,27.6%)in 87(92.6%sensitivity)of 94 samples from Korean CHB patients.When the results were compared with those obtained by the direct sequencing protocol,the LNA-RT-PCR method showed the same results in all but one of 87 positive detected samples(98.9%specificity).CONCLUSION The newly developed LNA-RT-PCR method could identify two rt269 polymorphisms,rt269L and rt269I,in CHB patients with genotype C2 infections.This method could be effectively used for the understanding of disease progression in genotype C2 endemic areas.

Implication of Oxidative Stress and Antioxidant Defence Systems in Symptomatic and Asymptomatic Plasmodium falciparum Malaria Infection among Children Aged 1 to 15 Years in the Mount Cameroon Area

It is known that the pathogenicity of Plasmodium induces the breakdown of haemoglobin, which leads to the induction of oxidative stress. This study aimed to identify the possible effects of oxidative stress and antioxidant defence systems in symptomatic and asymptomatic Plasmodium falciparum malaria infection in children (1 - 15 years old) in the Mount Cameroon vicinity. This cross-sectional study involved blood samples collected from 473 children and examined for malaria parasitaemia. Full blood counts were performed using an automated haemoanalyser. Serum oxidative stress status (malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) and vitamin C (Vit C)) were each determined by colorimetric enzymatic assays. The prevalence of malaria parasite infection was 32.1% among the participants. Out of that, 62.5% of patients with parasitaemia were symptomatic. Anaemia prevalence increased significantly with parasite density. MDA levels were significantly higher in patients with malaria symptoms than in those without symptoms. A significant and positive correlation was detected between MDA (r = 0.831, P < 0.05), NO (r = 0.779, P < 0.05), and malaria parasite density while, a significant and negative relationship occurred between parasite density and GSH (r = ?0.763, P < 0.05) and Vit C (r = ?0.826, P < 0.05) levels, SOD (r = ?0.621, P < 0.05) and CAT (r = ?0.817, P < 0.05) activities. The SOD activity and GSH level significantly decreased (P < 0.05) with an increase in the MDA levels. These findings showed that MDA and nitric oxide levels increased both in malaria participants with or without symptoms. A similar decrease in the antioxidant defence system was observed in both symptomatic and asymptomatic patients. Therefore, there is a need to develop public health policies that encourage routine diagnosis and treatment of malaria in seemingly healthy people (asymptomatic cases), and this will play an essential role in controlling malaria in tropical countries.

Ginsenoside compound-K attenuates OVX-induced osteoporosis via the suppression of RANKL-induced osteoclastogenesis and oxidative stress

Osteoporosis(OP),a systemic and chronic bone disease,is distinguished by low bone mass and destruction of bone microarchitecture.Ginsenoside Compound-K(CK),one of the metabolites of ginsenoside Rb1,has anti-aging,anti-inflammatory,anti-cancer,and hypolipidemic activities.We have demonstrated CK could promote osteogenesis and fracture healing in our previous study.However,the contribution of CK to osteoporosis has not been examined.In the present study,we investigated the effect of CK on osteoclastogenesis and ovariectomy(OVX)-induced osteoporosis.The results showed that CK inhibited receptor activator for nuclear factor-κB ligand(RANKL)-mediated osteoclast differentiation and reactive oxygen species(ROS)activity by inhibiting the phosphorylation of NF-κB p65 and oxidative stress in RAW264.7 cells.In addition,we also demonstrated that CK could inhibit bone resorption using bone marrow-derived macrophages.Furthermore,we demonstrated that CK attenuated bone loss by suppressing the activity of osteoclast and alleviating oxidative stress in vivo.Taken together,these results showed CK could inhibit osteoclastogenesis and prevent OVX-induced bone loss by inhibiting NF-κB signaling pathway.

Detection of Low-Risk and High-Risk Oncogenic Human Papillomavirus in Archived Tissues from ENT Tumors in Burkina Faso

Human papillomavirus (HPV) is classified into high-risk HPV (HR-HPV) and HPV (LR-HPV) according to their oncogenic potential. These viruses can be found in the cervix, vagina, vulva, anus and in the ENT sphere. HPV ENT infections can lead to benign or malignant tumors in which we could find both LR-HPV and HR-HPV genotypes. The objective of this study was to investigate the genotypes of HR-HPV and LR-HPV in archived tissue samples derived from both benign and malignant tumors of the ear, nose, and throat (ENT) in Ouagadougou, Burkina Faso. One hundred and twenty formalin-fixed, paraffin-embedded archived tissues of the ENT sphere from 26 benign tumors and 94 malignant tumors were included. The tissues were first deparaffinized with xylem. The extracted DNA was used to test for high-risk and low-risk HPV by Real-Time Multiplex PCR. HPV DNA was found in 57.7% (15/26) of benign tumors and 43.61% (41/94) of malignant tumors. The prevalence of HPV infection was 46.67% (56/120) in all tumors combined. The most common HPV genotypes found were HPV 11 (34.28%), HPV 6 (30%), HPV56 (14.28%) and HPV 33 (8.57%). There were 21.43% (12/56) cases of genotypes co-infections with 10 cases of double infection and 2 cases of triple infection. Both low-risk and high-risk HPV are found in ENT tumors with relatively high HPV prevalence.

Relationship between the Polymorphism of the GSTP1 (rs1695) Gene and Chronic Hepatitis B Infection in Ouagadougou, Burkina Faso

Introduction: Genetic polymorphisms of some Glutathione S-Transferase (GST) which encode the enzyme responsible for the biotransformation of drugs and xenobiotics, have been associated with the risk of several pathologies that can progress to cancer such as Hepatitis B. This study aims to characterize the impact of the rs1695 polymorphism of GSTP1 gene among people with chronic Hepatitis B infection in Burkina Faso. Methods: rs1695 polymorphisms of GSTP1 gene genotyping was performed for 50 people infected with chronic Hepatitis B virus and 124 healthy people with the PCR-RFLP method. Conventional PCR was used for DNA amplification and Alw26I enzyme was used for enzymatic digestion. Results: The results show that the frequencies of AA, AG and GG genotypes are respectively 31.00%, 36.80% and 32.20% in general the study population with a mutation rate of 50.57%. However, the incidence of the AA, AG and GG genotypes are respectively 30.64%, 38.71% and 30.64% among people with chronic Hepatitis B virus infection and 32.00%, 32.00% and 36.00% among healthy people. In cases, the frequencies of the A and G alleles are 48.00% and 52.00% respectively, and in controls 50.00% each. No statistical difference was found by comparing genotypic and allelic frequencies between cases and controls (p > 0.05). Conclusion: Our study allowed us to determine the rate of GSTP1 rs1695 genotypes in the study population, cases and controls. From our analyses, GSTP1 rs1695 is not associated to chronic Hepatitis B virus infection in Ouagadougou.

Diabetes mellitus:An overview of the types,prevalence,comorbidity,complication,genetics,economic implication,and treatment

Diabetes is one of the deadliest diseases.Due to its effects on the lives of people,it has attracted a lot of attention recently.The causes of the various forms of diabetes,including type 1 and type 2,were discussed along with how they affect those who have the disease.Younger people are more prone to type 1 diabetes than older people,who are more likely to develop type 2.The treatment options and strategies for the two forms of diabetes were also discussed in addition to how the disease affects the quality of life of people.Among several factors that were explained,it has been shown that people from low and middle-income countries are more prone to having diabetes.Additionally,the condition is more likely to affect some races more than others.It is associated with obesity.According to statistics,those who are poor are more severely affected by the disease.The progression of the disease over time has been associated with an increase in disability and mortality.

Transforming growth factor-beta 1 enhances discharge activity of cortical neurons

Transforming growth factor-beta 1(TGF-β1)has been extensively studied for its pleiotropic effects on central nervous system diseases.The neuroprotective or neurotoxic effects of TGF-β1 in specific brain areas may depend on the pathological process and cell types involved.Voltage-gated sodium channels(VGSCs)are essential ion channels for the generation of action potentials in neurons,and are involved in various neuroexcitation-related diseases.However,the effects of TGF-β1 on the functional properties of VGSCs and firing properties in cortical neurons remain unclear.In this study,we investigated the effects of TGF-β1 on VGSC function and firing properties in primary cortical neurons from mice.We found that TGF-β1 increased VGSC current density in a dose-and time-dependent manner,which was attributable to the upregulation of Nav1.3 expression.Increased VGSC current density and Nav1.3 expression were significantly abolished by preincubation with inhibitors of mitogen-activated protein kinase kinase(PD98059),p38 mitogen-activated protein kinase(SB203580),and Jun NH2-terminal kinase 1/2 inhibitor(SP600125).Interestingly,TGF-β1 significantly increased the firing threshold of action potentials but did not change their firing rate in cortical neurons.These findings suggest that TGF-β1 can increase Nav1.3 expression through activation of the ERK1/2-JNK-MAPK pathway,which leads to a decrease in the firing threshold of action potentials in cortical neurons under pathological conditions.Thus,this contributes to the occurrence and progression of neuroexcitatory-related diseases of the central nervous system.

Mitigating diabetes-related complications:Empowering metformin with cholecalciferol and taurine supplementation in type 2 diabetic rats

BACKGROUND Type 2 diabetes is one of the most prevalent chronic diseases worldwide,significantly impacting patients'quality of life.Current treatment options like metformin(MET)effectively counteract hyperglycemia but fail to alleviate diabetes-associated complications such as retinopathy,neuropathy,nephropathy,hepatopathy,and cardiovascular diseases.AIM To propose the supplementation of cholecalciferol(CHO)and taurine(TAU)to enhance MET efficacy in controlling diabetes while minimizing the risk of associated complications.METHODS The study involved sixty rats,including ten non-diabetic control rats and fifty experimental rats with type 2 diabetes induced by streptozotocin.The experimental rats were further subdivided into positive control and treatment subgroups.The four treatment groups were randomly allocated to a single MET treatment or MET combined with supplements either CHO,TAU,or both.RESULTS Diabetic rats exhibited elevated levels of glucose,insulin,Homeostasis Model Assessment of Insulin Resistance(HOMA-IR),glycated hemoglobin percentage,lipid markers,aspartate aminotransferase,and malondialdehyde,along with reduced levels of antioxidant enzymes(catalase and superoxide dismutase).The administration of CHO and TAU supplements alongside MET in diabetic rats led to a noticeable recovery of islet mass.The antioxidative,anti-inflammatory,and anti-apoptotic properties of the proposed combination therapy significantly ameliorated the aforementioned abnormalities.CONCLUSION The supplementation of CHO and TAU with MET showed the potential to significantly improve metabolic parameters and protect against diabetic complications through its antioxidative,anti-inflammatory,and antiapoptotic effects.

Genetic diversity and occult hepatitis B infection in Africa: A comprehensive review

BACKGROUND Occult hepatitis B infection(OBI)is a globally prevalent infection,with its frequency being influenced by the prevalence of hepatitis B virus(HBV)infection in a particular geographic region,including Africa.OBI can be transmitted th-rough blood transfusions and organ transplants and has been linked to the development of hepatocellular carcinoma(HCC).The associated HBV genotype influences the infection.AIM To highlight the genetic diversity and prevalence of OBI in Africa.METHODS This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and involved a comprehensive search on PubMed,Google Scholar,Science Direct,and African Journals Online for published studies on the prevalence and genetic diversity of OBI in Africa.RESULTS The synthesis included 83 articles,revealing that the prevalence of OBI varied between countries and population groups,with the highest prevalence being 90.9%in patients with hepatitis C virus infection and 38%in blood donors,indicating an increased risk of HBV transmission through blood transfusions.Cases of OBI reactivation have been reported following chemotherapy.Genotype D is the predominant,followed by genotypes A and E.CONCLUSION This review highlights the prevalence of OBI in Africa,which varies across countries and population groups.The study also demonstrates that genotype D is the most prevalent.

Beyond the stomach: An updated view of Helicobacter pylori pathogenesis, diagnosis, and treatment

Helicobacter pylori (H. pylori) is an extremely common, yet underappreciated, pathogen that is able to alter host physiology and subvert the host immune response, allowing it to persist for the life of the host. H. pylori is the primary cause of peptic ulcers and gastric cancer. In the United States, the annual cost associated with peptic ulcer disease is estimated to be $6 billion and gastric cancer kills over 700000 people per year globally. The prevalence of H. pylori infection remains high (&#x0003e; 50%) in much of the world, although the infection rates are dropping in some developed nations. The drop in H. pylori prevalence could be a double-edged sword, reducing the incidence of gastric diseases while increasing the risk of allergies and esophageal diseases. The list of diseases potentially caused by H. pylori continues to grow; however, mechanistic explanations of how H. pylori could contribute to extragastric diseases lag far behind clinical studies. A number of host factors and H. pylori virulence factors act in concert to determine which individuals are at the highest risk of disease. These include bacterial cytotoxins and polymorphisms in host genes responsible for directing the immune response. This review discusses the latest advances in H. pylori pathogenesis, diagnosis, and treatment. Up-to-date information on correlations between H. pylori and extragastric diseases is also provided.

The woodchuck as an animal model for pathogenesis and therapy of chronic hepatitis B virus infection

This review describes the woodchuck and the woodchuck hepatitis virus (WHV) as an animal model for pathogenesis and therapy of chronic hepatitis B virus (HBV) infection and disease in humans. The establishment of woodchuck breeding colonies, and use of laboratory-reared woodchucks infected with defined WHV inocula, have enhanced our understanding of the virology and immunology of HBV infection and disease pathogenesis, including major sequelae like chronic hepatitis and hepatocellular carcinoma. The role of persistent WHV infection and of viral load on the natural history of infection and disease progression has been firmly established along the way. More recently, the model has shed new light on the role of host immune responses in these natural processes, and on how the immune system of the chronic carrier can be manipulated therapeutically to reduce or delay serious disease sequelae through induction of the recovery phenotype. The woodchuck is an outbred species and is not well defined immunologically due to a limitation of available host markers. However, the recent development of several key host response assays for woodchucks provides experimental opportunities for further mechanistic studies of outcome predictors in neonatal- and adult-acquired infections. Understanding the virological and immunological mechanisms responsible for resolution of self-limited infection, andfor the onset and maintenance of chronic infection, will greatly facilitate the development of successful strategies for the therapeutic eradication of established chronic HBV infection. Likewise, the results of drug efficacy and toxicity studies in the chronic carrier woodchucks are predictive for responses of patients chronically infected with HBV. Therefore, chronic WHV carrier woodchucks provide a well-characterized mammalian model for preclinical evaluation of the safety and efficacy of drug candidates, experimental therapeutic vaccines, and immunomodulators for the treatment and prevention of HBV disease sequelae.

Role of peroxisome proliferators-activated receptors in the pathogenesis and treatment of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease （NAFLD） is highly prevalent and can result in nonalcoholic steatohepatitis （NASH） and progressive liver disease including cirrhosis and hepatocellular carcinoma. A growing body of literature implicates the peroxisome proliferators- activated receptors （PPARs） in the pathogenesis and treatment of NAFLD. These nuclear hormone receptors impact on hepatic triglyceride accumulation and insulin resistance. The aim of this review is to describe the data linking PPARα and PPART to NAFLD/NASH and to discuss the use of PPAR ligands for the treatment of NASH.

Measurement of circulating levels of VEGF-A,-C,and -D and their receptors,VEGFR-1 and -2 in gastric adenocarcinoma

AIM: To analyze the serum levels and prognostic significance of vascular endothelial growth factor (VEGF) -A,-C,and -D,and their receptors,VEGFR-1 and -2 in gastric adenocarcinomas. METHODS: The serum levels of VEGF family members were measured in 76 control subjects and 76 patients with gastric adenocarcinoma using an enzyme-linked immunosorbent assay (ELISA). These measurements were correlated with clinco-pathological features and survival rates. RESULTS: The serum levels of VEGF-A and its receptor,VEGFR-1,were signifi cantly higher in patients with gastric cancer than in healthy donors (t = 2.3,P = 0.02 and t = 4.2,P < 0.0001,respectively). In contrast,the serum levels of VEGF-D were signif icantly higher in control subjects than in patients (t = 2.9,P = 0.004). There was no significant difference in serum levels of VEGF-C and VEGFR-2 between patients and controls. VEGF-C was associated with advanced tumor stage and presence of metastasis. VEGFR-1 was associated with metastasis,advanced overall stage,tumor differentiation and survival. VEGFR-2 levels were associated with poor tumor differentiation. There was no significant prognostic value for any of the VEGF family members or their receptors except for VEGFR-1 where high levels were associated with a poor overall survival. CONCLUSION: Serum VEGF levels vary significantly in the same cohort of patients with variable clinico-pathological features and prognostic values. The simultaneous measurement of VEGF receptors levels in sera may overcome the limitations of a single biomarker assay.

Significance of endothelial dysfunction in the pathogenesis of early and delayed radiation enteropathy

This review summarizes the current state of knowledge regarding the role of endothelial dysfunction in the pathogenesis of early and delayed intestinal radiation toxicity and discusses various endothelial-oriented interventions aimed at reducing the risk of radiation enteropathy. Studies published in the biomedical literature during the past four decades and cited in PubMed, as well as clinical and laboratory data from our own research program are reviewed. The risk of injury to normal tissues limits the cancer cure rates that can be achieved with radiation therapy. During treatment of abdominal and pelvic tumors, the intestine is frequently a major close-limiting factor. Microvascular injury is a prominent feature of both early （inflammatory）, as well as delayed （fibroproliferative） radiation injuries in the intestine and in many other normal tissues. Evidence from our and other laboratories suggests that endothelial dysfunction, notably a deficiency of endothelial thrombomodulin, plays a key role in the pathogenesis of these radiation responses. Deficient levels of thrombomodulin cause loss of vascular thromboresistance, excessive activation of cellular thrombin receptors by thrombin, and insufficient activation of protein C, a plasma protein with anticoagulant, anti-inflammatory, and cytoprotective properties. These changes are presumed to be critically involved in many aspects of early intestinal radiation toxicity and may sustain the fibroproliferative processes that lead to delayed intestinal dysfunction, fibrosis, and clinical complications. In conclusion, injury of vascular endothelium is important in the pathogenesis of the intestinal radiation response. Endothelial-oriented interventions are appealing strategies to prevent or treat normal tissue toxicity associated with radiation treatment of cancer.